title: Pharmacologic inhibition of MEK signaling prevents growth of canine hemangiosarcoma.
abstract: Angiosarcoma is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. As a model for human angiosarcoma, we studied primary cells and tumorgrafts derived from canine hemangiosarcoma (HSA), which is also an endothelial malignancy with similar presentation and histology. Primary cells isolated from HSA showed constitutive extracellular signal-regulated kinase (ERK) activation. The mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor CI-1040 reduced ERK activation and the viability of primary cells derived from visceral, cutaneous, and cardiac HSA in vitro. HSA-derived primary cells were also sensitive to sorafenib, an inhibitor of B-Raf and multireceptor tyrosine kinases. In vivo, CI-1040 or PD0325901 decreased the growth of cutaneous cell-derived xenografts and cardiac-derived tumorgrafts. Sorafenib decreased tumor size in both in vivo models, although cardiac tumorgrafts were more sensitive. In human angiosarcoma, we noted that 50% of tumors stained positively for phosphorylated ERK1/2 and that the expression of several MEK-responsive transcription factors was upregulated. Our data showed that MEK signaling is essential for the growth of HSA in vitro and in vivo and provided evidence that the same pathways are activated in human angiosarcoma. This indicates that MEK inhibitors may form part of an effective therapeutic strategy for the treatment of canine HSA or human angiosarcoma, and it highlights the use of spontaneous canine cancers as a model of human disease.
authors.affiliation: Corresponding Author: Nicholas S. Duesbery, Laboratory of Cancer and Developmental Cell Biology, Van Andel Research Institute, 333 Bostwick Ave., NE, Grand Rapids, MI 49503. duesbery@vai.org.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Andersen
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Nickoloff
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Dykema
authors.forename: Elissa A
authors.initials: EA
authors.lastname: Boguslawski
authors.forename: Roman I
authors.initials: RI
authors.lastname: Krivochenitser
authors.forename: Roe E
authors.initials: RE
authors.lastname: Froman
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Dawes
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Baker
authors.forename: Dafydd G
authors.initials: DG
authors.lastname: Thomas
authors.forename: Debra A
authors.initials: DA
authors.lastname: Kamstock
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Kitchell
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Furge
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Duesbery
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006394:Hemangiosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000662:veterinary; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D010671:Phenylurea Compounds; D009536:Niacinamide; C506614:mirdametinib; D004159:Diphenylamine; D000077157:Sorafenib; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases